In this study of nearly half a million individuals followed for up to eight years, we found a modest but graded positive association between BMI and thyroid cancer. Specifically, overweight was related to a suggestive increase of nearly 30% in the risk of thyroid cancer and obesity was associated with an increase of 40% in the risk of thyroid cancer when compared to normal weight. The apparent adverse effect of adiposity on risk for thyroid cancer was evident for papillary and possibly follicular cancers, whereas no relation with BMI was seen for medullary thyroid cancers. The positive relation of BMI to total thyroid cancer was evident for men but not for women and was evident for Caucasians but not non-Caucasians. However, interaction tests suggested that these differences were not statistically significant. The positive relation of BMI to thyroid cancer was independent of other known or suspected risk factors for thyroid cancer we were able to control for, including age, smoking, and diet suggesting that avoidance of adiposity may play an important independent role in the prevention of thyroid cancer.
Our data showing a modest positive relation between BMI and total thyroid cancer is compatible with results from a recent meta-analysis17
of prospective studies on this topic. That meta-analysis17
included 3,587 thyroid cancer cases and found that each 5 kg/m2
increase in BMI was associated with a pooled RR of 1.14 (95% CI=1.06–1.23) for women and a pooled RR of 1.34 (95% CI=1.04–1.70) for men. Our findings with respect to histologic types of thyroid cancer are also consistent with a recent large prospective investigation from Norway18
that observed positive associations with BMI for papillary, follicular, and anaplastic thyroid cancers, whereas null or inverse associations with BMI were noted for medullary thyroid cancers. Heterogeneity in the relations of BMI to non-medullary versus medullary thyroid cancers may be explained by the distinct etiologies of thyroid cancer histologic types.19
While several prospective investigations support a positive relation of BMI to thyroid cancer,18, 20, 21
two cohort studies,22, 23
of which included both women and men whereas the other23
involved only men, reported a null association between BMI and thyroid cancer. Retrospective data24
from an Italian cohort of 1,333 morbidly obese patients aged 21 to 70 years who were referred for bariatric surgery revealed that thyroid cancer was the second most frequent site of cancer prevalence (18.6%) among those who presented with a cancer diagnosis at the time of referral, adding further evidence for a link between adiposity and thyroid cancer risk, although the latter finding could in part be due to selection bias because obese patients are seen by doctors more frequently than non-obese patients.
Although results differ somewhat among studies, case-control studies generally support a positive association between BMI and thyroid cancer. A pooled analysis of case-control investigations of BMI and thyroid cancer25
including 2,473 cases reported a pooled OR of 1.2 (95% CI=1.0–1.4) comparing extreme tertiles of BMI among women, but found no relation between BMI and thyroid cancer among men (pooled OR=1.0; 95% CI=0.8–1.4). The authors of the pooled analysis25
speculated that one possible reason for the weaker results among men than women was the considerably smaller sample size among men. Although not statistically significantly different, results from our study with an equal gender distribution of cases appeared stronger for men than women.
Several case-control studies have been published since the above-mentioned pooled analysis. A recent case-control study26
from New Caledonia observed an odds ratio (OR) of thyroid cancer of 1.85 (95% CI=1.02–3.35) for BMI of ≥35 kg/m2
compared to normal BMI among women, however, no relation in men (OR=1.04; 95% CI=0.28–3.79) comparing extreme categories of BMI. One case-control study27
among U.S. women found no relation between BMI and thyroid cancer but data were not presented. However, that study27
reported ORs of total and papillary thyroid cancer of 1.6 (95% CI=0.9–3.0) and 1.4 (95% CI=0.7–2.6), respectively, for weight gain of greater than 21 pounds between age 18 years and the reference age. One case-control study28
focusing on diet and thyroid cancer showed descriptive data suggesting a slightly higher BMI among thyroid cancer cases (25.4 kg/m2
) than controls (24.3 kg/m2
) but that comparison was based on an unadjusted analysis and the difference was only borderline statistically significant (p=0.05).
In contrast to the generally positive results for body mass in our and other studies, we found that physical activity was not associated with risk of total thyroid cancer in our cohort, although there was some suggestion of a positive relationship with the anaplastic cancer subtype. Available epidemiologic data regarding the relation of physical activity to thyroid cancer are sparse. One early case-control study29
found no statistically significant relation of occupational physical activity to thyroid cancer risk. A more recent case-control study30
among women reported an OR of papillary thyroid cancer of 0.76 (95% CI=0.59–0.98) for regular exercise during the two years before diagnosis compared to no regular exercise during that time period. Thus, the relation of physical activity to thyroid cancer remains unresolved.
Advantageous features of our study include its prospective design, a high follow-up rate, large sample size with a relatively sizeable number of cases, available data on thyroid cancer histologic types, and information on several potential thyroid cancer risk factors. Measurement error in assessing body size is not likely to be a concern because self-reported weight and height have been found to be highly accurate.31
Potential limitations of our study involve imprecise estimation of physical activity levels owing to the self-reported nature of our activity assessment,32
but, validation studies comparing physical activity assessments similar to those used in our cohort with referent methods indicate that the reliability and validity of our instrument is comparable to self-reported measures used in similar studies.33
A further potential shortcoming of our study is that we lacked sufficient numbers of thyroid cancer cases among non-Caucasians to evaluate whether the relation between BMI and total thyroid cancer varies according to ethnic or racial group. Some evidence suggests that associations with BMI differ by ethnic group. For example, a large prospective study21
of white and black U.S. veterans compared obese to non-obese men and found an RR of 1.92 (95% CI=1.09–3.40) for black men, whereas the RR for white men was less pronounced (corresponding RR=1.40; 95% CI=1.09–1.81). A particularly strong positive relation of BMI to thyroid cancer was observed in a case-control study among Melanesian women,26
showing an OR of 2.40 (95% CI=1.19–4.84) for individuals with a BMI of 30.-34.9 kg/m2
compared to those with a BMI of 18.5–24.9 kg/m2
. A prospective study of Korean men20
found a RR of thyroid cancer of 2.23 (95% CI=1.40–3.55) comparing men with a BMI of 27.0–29.9 kg/m2
to those with a BMI of 18.5–22.9 kg/m2
Our study lacked information on certain determinants of thyroid cancer, such as history of radiation exposure. Such factors could potentially confound the relation of adiposity or physical activity to thyroid cancer. Nonetheless, we carefully controlled for numerous potential confounding variables, including age, gender, race/ethnicity, education, smoking status, alcohol use, and oral contraceptive use among women. Moreover, inclusion of these risk factors in the models had little impact on the risk estimates, suggesting that regulation of these variables explains only a small portion of the apparent adverse effects of adiposity on thyroid cancer risk.
It has been hypothesized that the observed positive relation of adiposity to thyroid cancer risk may be due to detection bias because of more frequent examinations of the thyroid gland among overweight/obese than lean individuals.25
We lacked information on thyroid carcinoma size among cases in our study, which would have enabled us to uncover potential detection bias by focusing on relations with small sized thyroid carcinomas, which are more prone to be detected with more frequent examinations of the thyroid gland.34
Other methodologic biases do not likely explain the positive association with BMI seen in our data. Specifically, information on weight, height, and other exposures was collected prior to thyroid cancer diagnoses, which precluded bias ascribable to differential recall of weight, height, or physical activity by study participants with and without a subsequent diagnosis of thyroid cancer.
Biological mechanisms through which BMI may relate to thyroid cancer are speculative. Excess adiposity is related to increased insulin production, and insulin may enhance tumor growth by increasing free insulin-like growth factor (IGF)-1, which in turn stimulates cell proliferation and suppresses apoptosis and has been positively linked to thyroid cancer.35
Although hyperinsulinemia per se has not been implicated in thyroid carcinogenesis, hyperglycemia is directly associated with thyroid cancer.36
Among postmenopausal women, increased risk of thyroid cancer associated with adiposity may also be explained by increased production of endogenous estrogens in the adipose tissue37
because estrogens potentially promote thyroid carcinogenesis38
and have been found to be positively related to thyroid cancer.39
In addition, adiposity may increase thyroid cancer risk through its effects on thyroid stimulating hormone (TSH),40
which represents an independent predictor of thyroid malignancy.41
In summary, this study provides evidence for an adverse effect of adiposity on thyroid cancer risk. The positive relation with BMI was evident for papillary, and possibly follicular histologic subtypes of thyroid cancers. In contrast, based on only 15 cases, BMI did not appear to be associated with medullary thyroid cancers. The positive association between BMI and total thyroid cancer was evident for men but not for women, although the test of interaction indicated no statistically significant gender difference. No relation was observed between physical activity and total thyroid cancer although there was some suggestion of a positive relationship with the anaplastic cancer subtype. Future mechanistic studies should clarify potential biological mechanisms underlying the positive relation of adiposity to thyroid cancer risk.